This is a re-submission of a competing renewal which has the objective of evaluating the neural mechanisms of low back pain and which attempts to evaluate the potential utility of pharmacological agents designed to treat these disorders in animal models. The central hypothesis of this proposal is that the nucleus pulposus material from herniated discs or injury to the annulus causes inflammatory responses and release of algesic and neurotoxic chemicals that influence the activity of nerve cells within the spinal canal. It is hypothesized that the effects on nerve endings in disc and adjacent tissue lead to low back pain, while the effects on dorsal roots and dorsal root ganglia lead to sciatica. The specific aims of the proposal are to examine these mechanisms using neurophysiological, histological, immunocytochemical and molecular-biologic techniques. The applicants propose to determine whether chemicals known to exist in disc and inflamed tissue act to sensitize nerve endings in spinal cord roots. Additional goals are to determine if this central sensitization occurs in the rat spinal cord when vertebrae are exposed to nucleus pulposus or disc injury and to determine if the sympathetic nervous system contributes to this sensitization. The applicants believe that these approaches will lead to a better understanding of the role of disc injury and nuclear material in low back pain and sciatica, and that the outcomes may be useful in guiding treatment.